Treatment of cancer by chemotherapy frequently involves the use of a sequence of drugs, with the treating physician switching the treatment regime from one drug to another as resistance to each drug builds in turn. Failure of treatment can arise as a result of cross-resistance wherein a patient develops resistance to a first drug which in turn will generate resistance to treatment by a second drug. For example, in the treatment of breast cancer such cross resistance is often encountered when using the commonly-used drugs in the anthracycline and taxane families.
Doxorubicin (Adriamycin™) and paclitaxel (Taxol™) are both very effective agents used in the treatment of breast cancer. The former drug is an anthracycline which disrupts the uncoiling of DNA by topoisomerase II, intercalates between DNA strands, and causes DNA lesions, thereby interfering with DNA replication preferentially in rapidly dividing tumor cells. Doxorubicin can also kill tumor cells by stimulating Fas-mediated apoptosis through the induction of Fas ligand expression. Paclitaxel is a taxane which interferes with microtubule depolymerization in tumor cells resulting in an arrest of the cell cycle in mitosis followed by the induction of apoptosis. Adjuvant chemotherapy with anthracyclines and/or taxanes is now standard for treatment of breast cancer in lymph node positive women and in women with inflammatory breast cancer.
Despite their effectiveness, tumor resistance to paclitaxel or doxorubicin often develops, resulting in the failure of chemotherapy. Fewer than one-half of breast cancer patients respond to paclitaxel after failing anthracycline chemotherapy. A number of mechanisms have been identified by which resistance to doxorubicin can occur in tumor cells in vitro. These include the induction of drug transporters (both P-glycoprotein-P-gp, type ABCB1) and the multidrug resistance protein (MRP, type ABCC1), the down-regulation of topoisomerase II a activity, mutations in p53 activity, a disruption in the ability of doxorubicin to induce apoptosis, and the increased synthesis of both thymidylate synthase and the drug-conjugating enzyme glutathione-S-transferase. Similarly, resistance to paclitaxel in tumour cells in vitro can occur via a variety of mechanisms. These include the induction of P-gp expression, the acquisition of mutations in the α and β chains of tubulin, amplification of the serine-threonine kinase AURORA-A, cellular elevations in p53 levels, suppression of JNK-mediated Bcl-xL phosphorylation, downregulation of Bcl-2 (which binds paclitaxel), and upregulation of the Akt (PI-3-kinase) pathway.
Since paclitaxel is a very effective drug for the treatment of breast cancer and has a low toxicity profile relative to doxorubicin (when used in combination with granulocyte colony stimulating factor), breast cancer patients may be better served by treatment with paclitaxel before the administration of anthracyclines such as doxorubicin. This difference in tumor drug responsiveness in second-line chemotherapy may be related to differences in the capacities of paclitaxel and doxorubicin to induce cross-resistance to each other and possibly to other drugs. For example, longterm exposure of breast tumor cells to doxorubicin (resulting in resistance to the drug) may induce strong cross-resistance to paclitaxel, while similar exposure to paclitaxel may have less effect on doxorubicin cytotoxicity.
In general, there is a need for a method to determine the sequence of administration of chemotherapeutic drugs to minimize the possibility of cross-resistance. While empirical studies may be conducted to determine this, it is of course preferable to provide an in vitro approach that will accurately predict patient outcomes. This is particularly the case when it comes to determining the sequence of administration of three or more drugs, giving rise a large number of permutations and thus empirical testing becomes essentially impossible.